Molecular bases of epithelial cell invasion by Shigella flexneri

The pathogenesis of shigellosis is characterized by the capacity of the cau sative microorganism, Shigella, to invade the epithelial cells that compose the mucosal surface of the colon in humans. The invasive process encompass es several steps which can be summarized as follows: entry of bacteria into epithelial cells involves signalling pathways that elicit a macropinocitic event. Upon contact with the cell surface, S. flexneri activates a Mxi/Spa secretory apparatus encoded by two operons comprising about 25 genes locat ed on a large virulence plasmid of 220 kb. Through this specialized secreto ry apparatus, Ipa invasins are secreted, two of which (IpaB, 62 kDa and Ipa C, 42 kDa) form a complex which is itself able to activate entry via its in teraction with the host cell membrane. Interaction of this molecular comple x with the cell surface elicits major rearrangements of the host cell cytos keleton, essentially the polymerization of actin filaments that form bundle s supporting the membrane projections which achieve bacterial entry. Active recruitment of the protooncogene pp 60(c-src) has been demonstrated at the entry site with consequent phosphorylation of cortactin. Also, the small G TPase Rho is controlling the cascade of signals that allows elongation of a ctin filaments from initial nucleation foci underneath the cell membrane. T he regulatory signals involved as well as the proteins recruited indicate t hat Shigella induces the formation of an adherence plaque at the cell surfa ce in order to achieve entry. Once intracellular, the bacterium lyses its p hagocytic vacuole, escapes into the cytoplasm and starts moving the inducin g polar, directed polymerization of actin on its surface, due to the expres sion of IcsA, a 120 kDa outer membrane protein, which is localized at one p ole of the microorganism, following cleavage by SopA, a plasmid-encoded sur face protease. In the context of polarized epithelial cells, bacteria then reach the intermediate junction and engage their components, particularly t he cadherins, to form a protrusion which is actively internalized by the ad jacent cell. Bacteria then lyse the two membranes, reach the cytoplasmic co mpartment again, and resume actin-driven movement.